GRIA3

Glutamate receptor, ionotropic, AMPA 3
Identifiers
Symbols	GRIA3 ; GLUR-C; GLUR-K3; GLUR3; GLURC; GluA3; MRX94
External IDs	OMIM: 305915 MGI: 95810 HomoloGene: 37353 IUPHAR: 446 ChEMBL: 3595 GeneCards: GRIA3 Gene
Gene ontology Molecular function • AMPA glutamate receptor activity • extracellular-glutamate-gated ion channel activity Cellular component • plasma membrane • cell junction • dendrite • endocytic vesicle membrane • AMPA glutamate receptor complex • postsynaptic membrane Biological process • transport • glutamate receptor signaling pathway • synaptic transmission • ion transmembrane transport • ionotropic glutamate receptor signaling pathway • synaptic transmission, glutamatergic Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	2892	53623
Ensembl	ENSG00000125675	ENSMUSG00000001986
UniProt	P42263	Q9Z2W9
RefSeq (mRNA)	NM_000828	NM_001281929
RefSeq (protein)	NP_000819	NP_001268858
Location (UCSC)	Chr X: 123.18 – 123.49 Mb	Chr X: 41.4 – 41.68 Mb
PubMed search

Glutamate receptor 3 is a protein that in humans is encoded by the GRIA3 gene.^[1][2][3]

Function

Glutamate receptors are the predominant excitatory neurotransmitter receptors in the mammalian brain and are activated in a variety of normal neurophysiologic processes. These receptors are heteromeric protein complexes with multiple subunits, each possessing transmembrane regions, and all arranged to form a ligand-gated ion channel. The classification of glutamate receptors is based on their activation by different pharmacologic agonists. This gene belongs to a family of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptors. Alternative splicing at this locus results in several different isoforms which may vary in their signal transduction properties.^[3]

Interactions

GRIA3 has been shown to interact with GRIP1^[4] and PICK1.^[4]

RNA editing

Several ion channels and neurotransmitters receptors pre-mRNA as substrates for ADARs.^[5] This includes 5 subunits of the glutamate receptor: ionotropic AMPA glutamate receptor subunits (Glur2, Glur3, Glur4) and kainate receptor subunits (Glur5, Glur6). Glutamate gated ion channels are made up of four subunits per channel with each subunit contributing to the pore loop structure. The pore loop structure is related to that found in K⁺ channels (e.g., human K_v1.1 channel).^[6] The human K_v1.1 channel pre mRNA is also subject to A to I RNA editing.^[7] The function of the glutamate receptors is in the mediation of fast neurotransmission to the brain. The diversity of the subunits is determined, as well as rna splicing by RNA editing events of the individual subunits. This give rise to the necessarily high diversity of these receptors. GluR3 is a gene product of the GRIA3 gene and its pre-mRNA is subject to RNA editing.

Type

A to I RNA editing is catalyzed by a family of adenosine deaminases acting on RNA (ADARs) that specifically recognize adenosines within double-stranded regions of pre-mRNAs and deaminate them to inosine. Inosines are recognised as guanosine by the cells translational machinery. There are three members of the ADAR family ADARs 1-3, with ADAR1 and ADAR2 being the only enzymatically active members. ADAR3 is thought to have a regulatory role in the brain. ADAR1 and ADAR2 are widely expressed in tissues while ADAR3 is restricted to the brain. The double-stranded regions of RNA are formed by base-pairing between residues in the close to region of the editing site with residues usually in a neighboring intron but can be an exonic sequence. The region that base pairs with the editing region is known as an Editing Complementary Sequence (ECS)

Location

The pre-mRNA of this subunit is edited at one position. The R/G editing site is located in exon 13 between the M3 and M4 regions. Editing results in a codon change from an arginine (AGA) to a glycine (GGA). The location of editing corresponds to a bipartite ligand interaction domain of the receptor. The R/G site is found at amino acid 769 immediately before the 38-amino-acid-long flip and flop modules introduced by alternative splicing. Flip and Flop forms are present in both edited and nonedited versions of this protein.^[8] The editing complimentary sequence (ECS) is found in an intronic sequence close to the exon. The intronic sequence includes a 5' splice site. The predicted double stranded region is 30 base pairs in length. The adenosine residue is mismatched in genomically encoded transcript, however this is not the case following editing. Despite similar sequences to the Q/R site of GluR-B, editing a this site does not occur in GluR-3 pre-mRNA. Editing results in the targeted adenosine, which is mismatched prior to editing in the double-stranded RNA structure to become matched after editing. The intronic sequence involved contains a 5' donor splice site.^[8][9]

Conservation

Editing also occurs in rat.^[8]

Regulation

Editing of GluR-3 is regulated in rat brain from low levels in embryonic stage to a large increase in editing levels at birth. In humans, 80-90% of GRIA3 transcripts are edited.^[8] The absence of the Q/R site editing in this glutamate receptor subunit is due to the absence of necessary intronic sequence required to form a duplex.^[10]

Consequences

Structure

Editing results in a codon change from (AGA) to (GGA), an R to a G change at the editing site.^[8]

Function

Editing at R/G site allows for faster recovery from desensitisation. Unedited Glu-R at this site have slower recovery rates. Editing, therefore, allow sustained response to rapid stimuli. A crosstalk between editing and splicing is likely to occur here. Editing takes place before splicing. All AMPA receptors occur in flip and flop alternatively spliced variants. AMPA receptors that occur in the Flop form desenstise faster than the flip form.^[8] Editing is also thought to affect splicing at this site.

See also

• AMPA receptor

References

1. McNamara JO, Eubanks JH, McPherson JD, Wasmuth JJ, Evans GA, Heinemann SF (Jul 1992). "Chromosomal localization of human glutamate receptor genes". J Neurosci 12 (7): 2555–62. PMID 1319477.
2. Gecz J, Barnett S, Liu J, Hollway G, Donnelly A, Eyre H, Eshkevari HS, Baltazar R, Grunn A, Nagaraja R, Gilliam C, Peltonen L, Sutherland GR, Baron M, Mulley JC (Mar 2000). "Characterization of the human glutamate receptor subunit 3 gene (GRIA3), a candidate for bipolar disorder and nonspecific X-linked mental retardation". Genomics 62 (3): 356–68. doi:10.1006/geno.1999.6032. PMID 10644433.
3. "Entrez Gene: GRIA3 glutamate receptor, ionotrophic, AMPA 3".
4. Hirbec, Hélène; Perestenko Olga; Nishimune Atsushi; Meyer Guido; Nakanishi Shigetada; Henley Jeremy M; Dev Kumlesh K (May 2002). "The PDZ proteins PICK1, GRIP, and syntenin bind multiple glutamate receptor subtypes. Analysis of PDZ binding motifs". J. Biol. Chem. (United States) 277 (18): 15221–4. doi:10.1074/jbc.C200112200. ISSN 0021-9258. PMID 11891216.
5. Bass BL (2002). "RNA editing by adenosine deaminases that act on RNA". Annu. Rev. Biochem. 71: 817–46. doi:10.1146/annurev.biochem.71.110601.135501. PMC 1823043. PMID 12045112.
6. Seeburg PH, Single F, Kuner T, Higuchi M, Sprengel R (July 2001). "Genetic manipulation of key determinants of ion flow in glutamate receptor channels in the mouse". Brain Res. 907 (1-2): 233–43. doi:10.1016/S0006-8993(01)02445-3. PMID 11430906.
7. Bhalla T, Rosenthal JJ, Holmgren M, Reenan R (October 2004). "Control of human potassium channel inactivation by editing of a small mRNA hairpin". Nat. Struct. Mol. Biol. 11 (10): 950–6. doi:10.1038/nsmb825. PMID 15361858.
8. Lomeli H, Mosbacher J, Melcher T, Höger T, Geiger JR, Kuner T, Monyer H, Higuchi M, Bach A, Seeburg PH (December 1994). "Control of kinetic properties of AMPA receptor channels by nuclear RNA editing". Science 266 (5191): 1709–13. doi:10.1126/science.7992055. PMID 7992055.
9. Seeburg PH, Higuchi M, Sprengel R (May 1998). "RNA editing of brain glutamate receptor channels: mechanism and physiology". Brain Res. Brain Res. Rev. 26 (2-3): 217–29. doi:10.1016/S0165-0173(97)00062-3. PMID 9651532.
10. Herb A, Higuchi M, Sprengel R, Seeburg PH (March 1996). "Q/R site editing in kainate receptor GluR5 and GluR6 pre-mRNAs requires distant intronic sequences". Proc. Natl. Acad. Sci. U.S.A. 93 (5): 1875–80. doi:10.1073/pnas.93.5.1875. PMC 39875. PMID 8700852.

External sources

• http://darned.ucc.ie

Further reading

• Hollmann M, Hartley M, Heinemann S (1991). "Ca2+ permeability of KA-AMPA--gated glutamate receptor channels depends on subunit composition.". Science 252 (5007): 851–3. doi:10.1126/science.1709304. PMID 1709304.
• Rampersad V, Elliott CE, Nutt SL, et al. (1994). "Human glutamate receptor hGluR3 flip and flop isoforms: cloning and sequencing of the cDNAs and primary structure of the proteins.". Biochim. Biophys. Acta 1219 (2): 563–6. doi:10.1016/0167-4781(94)90090-6. PMID 7918660.
• Rogers SW, Andrews PI, Gahring LC, et al. (1994). "Autoantibodies to glutamate receptor GluR3 in Rasmussen's encephalitis.". Science 265 (5172): 648–51. doi:10.1126/science.8036512. PMID 8036512.
• Tomiyama M, Rodriguez-Puertas R, Cortés R, et al. (1997). "Differential regional distribution of AMPA receptor subunit messenger RNAs in the human spinal cord as visualized by in situ hybridization.". Neuroscience 75 (3): 901–15. doi:10.1016/0306-4522(96)00321-1. PMID 8951883.
• Osten P, Srivastava S, Inman GJ, et al. (1998). "The AMPA receptor GluR2 C terminus can mediate a reversible, ATP-dependent interaction with NSF and alpha- and beta-SNAPs.". Neuron 21 (1): 99–110. doi:10.1016/S0896-6273(00)80518-8. PMID 9697855.
• Srivastava S, Osten P, Vilim FS, et al. (1998). "Novel anchorage of GluR2/3 to the postsynaptic density by the AMPA receptor-binding protein ABP.". Neuron 21 (3): 581–91. doi:10.1016/S0896-6273(00)80568-1. PMID 9768844.
• Hayashi T, Umemori H, Mishina M, Yamamoto T (1999). "The AMPA receptor interacts with and signals through the protein tyrosine kinase Lyn.". Nature 397 (6714): 72–6. doi:10.1038/16269. PMID 9892356.
• Amir R, Dahle EJ, Toriolo D, Zoghbi HY (2000). "Candidate gene analysis in Rett syndrome and the identification of 21 SNPs in Xq.". Am. J. Med. Genet. 90 (1): 69–71. doi:10.1002/(SICI)1096-8628(20000103)90:1<69::AID-AJMG12>3.0.CO;2-W. PMID 10602120.
• Aruscavage PJ, Bass BL (2000). "A phylogenetic analysis reveals an unusual sequence conservation within introns involved in RNA editing.". RNA 6 (2): 257–69. doi:10.1017/S1355838200991921. PMC 1369911. PMID 10688364.
• Gahring L, Carlson NG, Meyer EL, Rogers SW (2001). "Granzyme B proteolysis of a neuronal glutamate receptor generates an autoantigen and is modulated by glycosylation.". J. Immunol. 166 (3): 1433–8. doi:10.4049/jimmunol.166.3.1433. PMID 11160179.
• Liu QJ, Gong YQ, Chen BX, et al. (2001). "[Linkage analysis and mutation detection of GRIA3 in Smith--Fineman--Myers syndrome]". Yi Chuan Xue Bao 28 (11): 985–90. PMID 11725645.
• Hirbec H, Perestenko O, Nishimune A, et al. (2002). "The PDZ proteins PICK1, GRIP, and syntenin bind multiple glutamate receptor subtypes. Analysis of PDZ binding motifs.". J. Biol. Chem. 277 (18): 15221–4. doi:10.1074/jbc.C200112200. PMID 11891216.
• Wyszynski M, Kim E, Dunah AW, et al. (2002). "Interaction between GRIP and liprin-alpha/SYD2 is required for AMPA receptor targeting.". Neuron 34 (1): 39–52. doi:10.1016/S0896-6273(02)00640-2. PMID 11931740.
• Tomiyama M, Rodríguez-Puertas R, Cortés R, et al. (2002). "Flip and flop splice variants of AMPA receptor subunits in the spinal cord of amyotrophic lateral sclerosis.". Synapse 45 (4): 245–9. doi:10.1002/syn.10098. PMID 12125045.
• Strausberg RL, Feingold EA, Grouse LH, et al. (2003). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences.". Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–903. doi:10.1073/pnas.242603899. PMC 139241. PMID 12477932.
• Ganor Y, Besser M, Ben-Zakay N, et al. (2003). "Human T cells express a functional ionotropic glutamate receptor GluR3, and glutamate by itself triggers integrin-mediated adhesion to laminin and fibronectin and chemotactic migration.". J. Immunol. 170 (8): 4362–72. doi:10.4049/jimmunol.170.8.4362. PMID 12682273.
• Flajolet M, Rakhilin S, Wang H, et al. (2004). "Protein phosphatase 2C binds selectively to and dephosphorylates metabotropic glutamate receptor 3.". Proc. Natl. Acad. Sci. U.S.A. 100 (26): 16006–11. doi:10.1073/pnas.2136600100. PMC 307683. PMID 14663150.
• Kolleker A, Zhu JJ, Schupp BJ, et al. (2004). "Glutamatergic plasticity by synaptic delivery of GluR-B(long)-containing AMPA receptors.". Neuron 40 (6): 1199–212. doi:10.1016/S0896-6273(03)00722-0. PMID 14687553.

External links

• GRIA3 protein, human at the US National Library of Medicine Medical Subject Headings (MeSH)
• "DARNED".

This article incorporates text from the United States National Library of Medicine, which is in the public domain.